Endotoxin Effects on Cardiac and Renal Functions and Cardiorenal Syndromes

Gram-negative sepsis is a major cause of morbidity and mortality in critical ill patients. Recent findings in molecular biology and in signaling pathways have enhanced our understanding of its pathogenesis and opened up opportunities of innovative therapeutic approaches. Endotoxin plays a pivotal role in the pathogenesis of multi-organ dysfunction in the setting of gram-negative sepsis. Indeed, heart and kidney impairments seem to be induced by the release of circulating pro-inflammatory and pro-apoptotic mediators triggered by endotoxin interaction with immune cells. These molecules are responsible for cellular apoptosis, autophagy, cell cycle arrest, and microRNAs activation. Therefore, the early identification of sepsis-associated acute kidney injury and heart dysfunction may improve the patient clinical outcome. In this report, we will consider the role of endotoxin in the pathogenesis of sepsis, its effects on both cardiac and renal functions, and the interactions between these 2 systems in the setting of cardiorenal syndromes (CRS), particularly in CRS type 5. Finally, we will discuss the possible role of extracorporeal therapies in reducing endotoxin levels.

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Autophagy Function and Regulation in Kidney Disease

Biomolecules ◽

10.3390/biom10010100 ◽

2020 ◽

Vol 10 (1) ◽

pp. 100 ◽

Cited By ~ 5

Author(s):

Gur P. Kaushal ◽

Kiran Chandrashekar ◽

Luis A. Juncos ◽

Sudhir V. Shah

Keyword(s):

Cell Death ◽

Renal Injury ◽

Mammalian Target Of Rapamycin ◽

Kidney Injury ◽

Therapeutic Approaches ◽

Regulated Necrosis ◽

Atg Genes ◽

Cellular Components ◽

The Impact

Autophagy is a dynamic process by which intracellular damaged macromolecules and organelles are degraded and recycled for the synthesis of new cellular components. Basal autophagy in the kidney acts as a quality control system and is vital for cellular metabolic and organelle homeostasis. Under pathological conditions, autophagy facilitates cellular adaptation; however, activation of autophagy in response to renal injury may be insufficient to provide protection, especially under dysregulated conditions. Kidney-specific deletion of Atg genes in mice has consistently demonstrated worsened acute kidney injury (AKI) outcomes supporting the notion of a pro-survival role of autophagy. Recent studies have also begun to unfold the role of autophagy in progressive renal disease and subsequent fibrosis. Autophagy also influences tubular cell death in renal injury. In this review, we reported the current understanding of autophagy regulation and its role in the pathogenesis of renal injury. In particular, the classic mammalian target of rapamycin (mTOR)-dependent signaling pathway and other mTOR-independent alternative signaling pathways of autophagy regulation were described. Finally, we summarized the impact of autophagy activation on different forms of cell death, including apoptosis and regulated necrosis, associated with the pathophysiology of renal injury. Understanding the regulatory mechanisms of autophagy would identify important targets for therapeutic approaches.

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Mitochondrial dysfunction and the AKI-to-CKD transition

AJP Renal Physiology ◽

10.1152/ajprenal.00285.2020 ◽

2020 ◽

Vol 319 (6) ◽

pp. F1105-F1116

Author(s):

Mingzhu Jiang ◽

Mi Bai ◽

Juan Lei ◽

Yifan Xie ◽

Shuang Xu ◽

...

Keyword(s):

Therapeutic Strategy ◽

Kidney Diseases ◽

Kidney Injury ◽

Mitochondrial Homeostasis ◽

Cycle Arrest ◽

Persistent Inflammation ◽

Acute Injuries ◽

Nephron Loss ◽

Effective Therapeutic Strategy

Acute kidney injury (AKI) has been widely recognized as an important risk factor for the occurrence and development of chronic kidney disease (CKD). Even milder AKI has adverse consequences and could progress to renal fibrosis, which is the ultimate common pathway for various terminal kidney diseases. Thus, it is urgent to develop a strategy to hinder the transition from AKI to CKD. Some mechanisms of the AKI-to-CKD transition have been revealed, such as nephron loss, cell cycle arrest, persistent inflammation, endothelial injury with vascular rarefaction, and epigenetic changes. Previous studies have elucidated the pivotal role of mitochondria in acute injuries and demonstrated that the fitness of this organelle is a major determinant in both the pathogenesis and recovery of organ function. Recent research has suggested that damage to mitochondrial function in early AKI is a crucial factor leading to tubular injury and persistent renal insufficiency. Dysregulation of mitochondrial homeostasis, alterations in bioenergetics, and organelle stress cross talk contribute to the AKI-to-CKD transition. In this review, we focus on the pathophysiology of mitochondria in renal recovery after AKI and progression to CKD, confirming that targeting mitochondria represents a potentially effective therapeutic strategy for the progression of AKI to CKD.

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Genetics and Inflammation in Endometriosis: Improving Knowledge for Development of New Pharmacological Strategies

International Journal of Molecular Sciences ◽

10.3390/ijms22169033 ◽

2021 ◽

Vol 22 (16) ◽

pp. 9033

Author(s):

Elisa Giacomini ◽

Sabrina Minetto ◽

Letizia Li Li Piani ◽

Luca Pagliardini ◽

Edgardo Somigliana ◽

...

Keyword(s):

Signaling Pathways ◽

Immune Cells ◽

Immune Cell ◽

Extracellular Vesicle ◽

Cellular Adhesion ◽

Therapeutic Approaches ◽

Therapeutic Alternative ◽

Per Se ◽

Functional Pathways

According to a rich body of literature, immune cell dysfunctions, both locally and systemically, and an inflammatory environment characterize all forms of endometriosis. Alterations in transcripts and proteins involved in the recruitment of immune cells, in the interaction between cytokines and their receptors, cellular adhesion and apoptosis have been demonstrated in endometriotic lesions. The objective of this narrative review is to provide an overview of the components and mechanisms at the intersection between inflammation and genetics that may constitute vanguard therapeutic approaches in endometriosis. The GWAS technology and pathway-based analysis highlighted the role of the MAPK and the WNT/β-catenin cascades in the pathogenesis of endometriosis. These signaling pathways have been suggested to interfere with the disease establishment via several mechanisms, including apoptosis, migration and angiogenesis. Extracellular vesicle-associated molecules may be not only interesting to explain some aspects of endometriosis progression, but they may also serve as therapeutic regimens per se. Immune/inflammatory dysfunctions have always represented attractive therapeutic targets in endometriosis. These would be even more interesting if genetic evidence supported the involvement of functional pathways at the basis of these alterations. Targeting these dysfunctions through next-generation inhibitors can constitute a therapeutic alternative for endometriosis.

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Regulation of Blood and Lymphatic Vessels by Immune Cells in Tumors and Metastasis

Annual Review of Physiology ◽

10.1146/annurev-physiol-020518-114721 ◽

2019 ◽

Vol 81 (1) ◽

pp. 535-560 ◽

Cited By ~ 8

Author(s):

Massimiliano Mazzone ◽

Gabriele Bergers

Keyword(s):

Immune Cells ◽

Lymphatic Vessels ◽

Tumor Vasculature ◽

Therapeutic Approaches ◽

Cancer Hallmarks ◽

Adaptive Immune ◽

Adaptive Immune Cells ◽

Vessel Growth ◽

Lymphatic Vasculature

Research over the last decades has provided strong evidence for the pivotal role of the tumor-associated blood and lymphatic vasculature in supporting immunoevasion and in subverting T cell–mediated immunosurveillance. Conversely, tumor blood and lymphatic vessel growth is in part regulated by the immune system, with infiltrating innate as well as adaptive immune cells providing both immunosuppressive and various angiogenic signals. Thus, tumor angiogenesis and escape of immunosurveillance are two cancer hallmarks that are tightly linked and interregulated by cell constituents from compartments secreting both chemokines and cytokines. In this review, we discuss the implication and regulation of innate and adaptive immune cells in regulating blood and lymphatic angiogenesis in tumor progression and metastases. Moreover, we also highlight novel therapeutic approaches that target the tumor vasculature as well as the immune compartment to sustain and improve therapeutic efficacy in cancer.

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Protective role of endothelial calpain knockout in lipopolysaccharide-induced acute kidney injury via attenuation of the p38-iNOS pathway and NO/ROS production

Experimental & Molecular Medicine ◽

10.1038/s12276-020-0426-9 ◽

2020 ◽

Vol 52 (4) ◽

pp. 702-712

Author(s):

Zhifeng Liu ◽

Jingjing Ji ◽

Dong Zheng ◽

Lei Su ◽

Tianqing Peng ◽

...

Keyword(s):

Acute Kidney Injury ◽

Caspase 3 ◽

Kidney Injury ◽

Protective Role ◽

Inos Expression ◽

Calpain Inhibitor ◽

Ros Production ◽

Enos Expression ◽

Cellular Apoptosis

Abstract To explore the role of calpain and its signaling pathway in lipopolysaccharide (LPS)-induced acute kidney injury (AKI), animal models of endotoxemia were established by administration of LPS to mice with endothelial-specific Capn4 knockout (TEK/Capn4−/−), mice with calpastatin (an endogenous calpain inhibitor) overexpression (Tg-CAST) and mice with myeloid-specific Capn4 knockout (LYZ/Capn4−/−). Mouse pulmonary microvascular endothelial cells (PMECs) were used as a model of the microvascular endothelium and were stimulated with LPS. Renal function, renal inducible nitric oxide synthase (iNOS) and endothelial NOS (eNOS) expression, cellular apoptosis, plasma and renal levels of NO and reactive oxygen species (ROS), and phosphorylation of mitogen-activated protein kinase (MAPK) family members (p38, ERK1/2, and JNK1/2) were examined. Moreover, a calpain inhibitor, calpastatin overexpression adenoviruses and MAPK inhibitors were used. Significant renal dysfunction was induced by LPS stimulation, and recovery was observed in TEK/Capn4−/− and Tg-CAST mice but not in LYZ/Capn4−/− mice. Endothelial Capn4 knockout also abrogated the LPS-induced increases in renal iNOS expression, caspase-3 activity and apoptosis and plasma and renal NO and ROS levels but did not obviously affect renal eNOS expression. Moreover, LPS increased both calpain and caspase-3 activity, and only the expression of iNOS in PMECs was accompanied by increased phosphorylation of p38 and JNK. Inhibiting calpain activity or p38 phosphorylation alleviated the increased iNOS expression, NO/ROS production, and cellular apoptosis induced by LPS. These results suggest that endothelial calpain plays a protective role in LPS-induced AKI by inhibiting p38 phosphorylation, thus attenuating iNOS expression and further decreasing NO and ROS overproduction-induced endothelial apoptosis.

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Role of Immune Cells in Acute Kidney Injury and Repair

Nephron ◽

10.1159/000477181 ◽

2017 ◽

Vol 137 (4) ◽

pp. 282-286 ◽

Cited By ~ 30

Author(s):

Sul A Lee ◽

Sanjeev Noel ◽

Mohanraj Sadasivam ◽

Abdel R.A. Hamad ◽

Hamid Rabb

Keyword(s):

Acute Kidney Injury ◽

Immune Cells ◽

Kidney Injury ◽

Injury And Repair

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Acute kidney injury

Care of the Acutely Ill Adult ◽

10.1093/med/9780198793458.003.0005 ◽

2020 ◽

pp. 135-156

Author(s):

Cristina Osorio ◽

Theofanis Fotis

Keyword(s):

Acute Kidney Injury ◽

Kidney Function ◽

Nursing Care ◽

Early Identification ◽

Kidney Injury ◽

Anatomy And Physiology ◽

Renal Replacement Therapies ◽

Life Threatening ◽

Kidney Anatomy

Assessing and supporting kidney function is an integral aspect of acute care. AKI (acute kidney injury) may cause sudden, life-threatening biochemical disturbances and hence the early identification, escalation to treatment and management of AKI is an important focus in the management of acutely ill patients. This chapter reviews kidney anatomy and physiology followed by the nursing care involved in assessing and managing abnormal kidney function. The focus is on relevance and applicability to clinical practice and understanding of kidney function as protective measures and early detection of anomalies greatly reduces the risk of acute kidney injury. Common renal pathologies are explored and the role of renal replacement therapies is discussed.

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NKT Cells in Sepsis

Clinical and Developmental Immunology ◽

10.1155/2010/414650 ◽

2010 ◽

Vol 2010 ◽

pp. 1-10 ◽

Cited By ~ 12

Author(s):

Briana Leung ◽

Hobart W. Harris

Keyword(s):

Septic Shock ◽

T Cells ◽

Immune Cells ◽

Natural Killer T Cells ◽

Nkt Cells ◽

Innate And Adaptive Immunity ◽

Gram Negative ◽

Sepsis And Septic Shock ◽

Killer T Cells

Sepsis is currently a leading cause of death in hospital intensive care units. Previous studies suggest that the pathophysiology of sepsis involves the hyperactivation of complex proinflammatory cascades that include the activation of various immune cells and the exuberant secretion of proinflammatory cytokines by these cells. Natural killer T-cells (NKTs) are a sublineage of T cells that share characteristics of conventional T cells and NK cells and bridge innate and adaptive immunity. More recently, NKT cells have been implicated in microbial immunity, including the onset of sepsis. Moreover, apolipoprotein E (apoE), a component of triglyceride-rich lipoproteins, has been shown to be protective in endotoxemia and gram-negative infections in addition to its well-known role in lipid metabolism. Here, we will review the role of NKT cells in sepsis and septic shock, the immunoregulatory role of apoE in the host immune response to infection, and propose a mechanism for this immunoregulation.

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The Role of Urinary Biomarkers as Diagnostic and Prognostic Predictors of Acute Kidney Injury Associated With Vancomycin

Frontiers in Pharmacology ◽

10.3389/fphar.2021.705636 ◽

2021 ◽

Vol 12 ◽

Author(s):

Durval Sampaio de Souza Garms ◽

Karina Zanchetta Cardoso Eid ◽

Emmanuel A. Burdmann ◽

Lia Junqueira Marçal ◽

Leila Antonângelo ◽

...

Keyword(s):

Cell Cycle ◽

Acute Kidney Injury ◽

Cell Cycle Arrest ◽

Kidney Function ◽

Kidney Injury ◽

Urinary Biomarkers ◽

Urinary Ngal ◽

Prognostic Predictors ◽

Cycle Arrest

Introduction: The incidence of acute kidney injury (AKI) related to vancomycin is variable, and several risk factors related to the treatment and patients may explain the nephrotoxicity. The role of urinary biomarkers in AKI related to vancomycin is unknown.Objective: The aim of this study was to evaluate the role of urinary IL-18, KIM-1, NGAL, TIMP-2, and IGFBP7 as diagnostic and prognostic predictors of AKI related to vancomycin.Methods: A prospective cohort study of patients receiving vancomycin and admitted to wards of a public university hospital from July 2019 to May 2020 was performed. We excluded patients that had AKI before starting vancomycin, hemodynamic instability, inability to collect urine, and chronic kidney disease stage 5.Results: Ninety-four patients were included, and the prevalence of AKI was 24.5%, while the general mortality was 8.7%. AKI occurred 11 ± 2 days after the first vancomycin dose. The most frequent KDIGO stage was 1 (61%). There was no difference between patients who developed and did not develop AKI due to gender, length of hospital stay, dose, and time of vancomycin use. Logistic regression identified age (OR 6.6, CI 1.16–38.22, p = 0.03), plasmatic vancomycin concentrations between 96 and 144 h (OR 1.18, CI 1.04-1.40, p = 0.04), and urinary NGAL levels between 96 and 144 h (OR 1.123, CI 1.096–1.290, p = 0.03) as predictors of AKI. The time of vancomycin use (OR 4.61, CI 1.11–22.02, p = 0.03), higher plasmatic vancomycin concentrations between 192 and 240 h (OR 1.02, CI 0.98–1.06, p = 0.26), and higher cell cycle arrest urinary biomarkers TIMP-2 multiplied by IGFBP-7 between 144 and 192 h (OR 1.33, CI 1.10–1.62, p = 0.02; OR 1.19, CI 1.09–1.39, p = 0.04, respectively) were identified as prognostic factors for non-recovery of kidney function at discharge.Conclusion: AKI related to vancomycin was frequent in patients hospitalized in wards. Age, plasmatic vancomycin concentrations, and NGAL between 96 and 144 h were identified as predictors of AKI related to vancomycin use. Plasmatic vancomycin concentrations and urinary NGAL were predictors of AKI diagnosis within the next 5 days. The urinary biomarkers of cell cycle arrest TIMP-2 and IGFBP-7 and the duration of vancomycin use were associated with non-recovery of kidney function at hospital discharge moment.

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Abstract 175: The Role of Axl in Accumulation of Immune Cells in Kidney and the Onset of Hypertension

Hypertension ◽

10.1161/hyp.60.suppl_1.a175 ◽

2012 ◽

Vol 60 (suppl_1) ◽

Author(s):

Sri Nagarjun Batchu ◽

Angie Hughson ◽

Janice Gerloff ◽

Deborah J Fowell ◽

Vyacheslav A Korshunov

Keyword(s):

Blood Pressure ◽

Immune Cells ◽

Immune Cell ◽

Kidney Injury ◽

Wild Type ◽

Protein Levels ◽

Immune Cell Subsets ◽

Early Increase ◽

Salt Hypertension

Introduction: Gas6/Axl pathway contributes to elevation of blood pressure. Immune cells are implicated in initiation and maintenance of hypertension. In this study we aimed to investigate the role of Axl in immune cells on kidney injury and initiation of hypertension. Methods and Results: Deoxycorticosterone-acetate (DOCA; 75mg, 60days release) and salt hypertension was induced for 1wk or 6wks in four groups of Axl chimeras (n=4-5) that were generated by bone marrow (BM) transplant. Multi parameter flow cytometry was used to quantify five major immune cell subsets in digested kidneys from Axl chimeras. Systolic blood pressure (SBP) increased by 30mmHg in Axl+/+ →Axl+/+, Axl-/- →Axl-/- and Axl+/+ →Axl-/- mice after 1wk of DOCA-salt. However, chimeras that lack Axl in the BM cells (Axl-/- →Axl+/+) showed reduction in early increase in SBP (16+2mmHg). We observed a significant decrease in urine protein levels in Axl-/- →Axl+/+ (0.3+0.1μg/μl) compared to other Axl chimeras (∼0.7μg/μl) after 1wk of DOCA-salt. Kidney glomeruli areas were reduced in Axl-/- →Axl+/+ (4,143+229μm 2 ) compared to other Axl chimeras (∼6,000μm 2 ) after 6wks of DOCA-salt. Kidneys from Axl-/- →Axl-/- showed an increase in total leukocytes (8 vs. 4%), B cells (29 vs. 12%) and decrease in monocytes/macrophages (16 vs. 22%) and dendritic cells (5 vs. 10%) compared to Axl+/+ →Axl+/+. Moreover, Axl-/- →Axl+/+ showed further increase in leukocytes (17%), B (39%) and dendritic (13%) cells in kidneys compared to other Axl chimeras. In addition a small percentage of wild type T cells was increased in the kidneys from Axl-/- →Axl+/+ chimeras. Conclusions: These findings suggest that Axl expression in BM-derived cells is critical for kidney injury in DOCA-salt hypertension. Axl-dependent pathways regulate immune cell populations in the kidneys during initiation of hypertension. This study was supported by HL105623 grant (VAK)

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